GW Pharmaceuticals plc and Otsuka Pharmaceutical Development & Commercialization, Inc., have reported the top-line results from the first of three Phase 3 trials for the investigational product Sativex in the treatment of pain in patients with advanced cancer who experience inadequate analgesia during optimized chronic opioid therapy. In this first trial, Sativex (as adjunctive treatment to optimized chronic opioid therapy) did not meet the primary endpoint of demonstrating a statistically significant difference from placebo.

“Although we missed the primary endpoint in this trial, based upon the positive data seen in the Phase 2 program, we remain confident in the ability for Sativex to relieve cancer pain in this patient population”, stated Justin Gover, GW’s Chief Executive Officer. “We have two additional pivotal Phase 3 trials ongoing which, if positive, would still allow us to submit a New Drug Application with the US FDA. We look forward to results from these two further studies later this year.”

Efficacy

The primary efficacy measure of the study was a patient assessment of pain using a 0-to-10 Numeric Rating Scale (NRS) which was analysed using percent improvement from baseline as the primary analysis. In addition, improvement was also analysed using a cumulative proportion of responders analysis (CPRA), which analyses the full range of responses achieved across the entire patient population within a trial. In this trial, these analyses did not show a statistically significant difference between Sativex and placebo. The secondary endpoints followed the pattern of the primary endpoint. In this study, the United States was the largest single recruiting country. Although not statistically significant, the efficacy data from U.S. sites showed more positive trends than those in non-U.S. sites. This is consistent with data from the Phase 2b trial.

Safety

The safety profile of Sativex in this Phase 3 trial was consistent with previous studies in this patient population. Overall, Sativex was well tolerated. The only adverse events reported at greater than 10% for the Sativex population were neoplasm progression (16% on Sativex vs 18% on placebo) and somnolence (12% on Sativex vs 4% on placebo). The other most frequently reported adverse event on Sativex was dizziness (8% on Sativex vs 5% on placebo). Otherwise, there was little difference in the adverse event pattern between Sativex and placebo. There were 38 (19%) withdrawals due to adverse events on Sativex compared with 29 (15%) on placebo. Commenting on the results, Dr. Marie Fallon, Professor of Palliative Care, University of Edinburgh and the principal investigator stated, “We believe that cannabinoid therapy offers a potentially novel approach as a co-analgesic to provide pain relief beyond opioid therapy. Too many patients with advanced cancer do not attain adequate pain relief from an opioid regimen, or experience unacceptable opioid side effects. Whilst I am naturally disappointed that this first trial did not achieve its primary endpoint, I remain optimistic about the potential of Sativex and look forward to the upcoming data from the remaining Sativex Phase 3 trials later this year.”

Phase 3 Trial Design

This randomized double-blind placebo-controlled parallel-group study recruited a total of 399 patients at clinical sites in the U.S., Mexico and Europe. This trial evaluated Sativex at a dose range of 3-to-10 sprays per day over a 5-week treatment period with an additional 5-to-14 day stabilization period at the beginning of the trial and a one-week follow-up at the end of the trial. Patients received the active investigational agent or placebo as add-on treatment to optimized opioid therapy and remained on stable doses of their background opioid therapy during the study. Following completion of the randomized phase, all patients were eligible to enter a long-term extension trial.

This study is the first of three Phase 3 trials carried out by GW and Otsuka as part of the development program aimed at securing regulatory approval for Sativex in cancer pain from the FDA and other regulatory authorities around the world.

A second Phase 3 pivotal trial, identical to the first, is expected to report top line results in the second quarter of 2015. GW and Otsuka are also in the process of conducting a third Phase 3 trial, which is expected to enroll approximately 540 patients and designed to provide additional information on the effects of Sativex in treating opioid-resistant cancer pain. The third Phase 3 trial differs in design from the first two trials, employing a two-part “enriched trial design” akin to that which was successfully employed in the Sativex MS spasticity trials program in Europe. The results of this third trial are expected towards the end of 2015. GW will continue to be the holder of the IND until the filing of a New Drug Application, which will be in Otsuka’s name.

Phase 2 Data

Sativex has previously completed a Phase 2b dose ranging study and Phase 2a study. In these prior studies, Sativex showed statistically significant improvements versus placebo using the same primary measure as in the Phase 3 trial.

Sativex in Multiple Sclerosis

Sativex is approved for the treatment of spasticity due to multiple sclerosis in 27 countries outside the U.S. In the U.S., a request for Special Protocol Assessment has been submitted to the FDA for a proposed single Phase 3 study in this indication.